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Fulltext The Role of Calcium in Wound Healing

Subramaniam T, Fauzi MB, Lokanathan Y, Law JX

Int J Mol Sci, 2021 Jun 17;22(12).
PMID: 34204292 DOI: 10.3390/ijms22126486

Skin injury is quite common, and the wound healing is a complex process involving many types of cells, the extracellular matrix, and soluble mediators. Cell differentiation, migration, and proliferation are essential in restoring the integrity of the injured tissue. Despite the advances in science and technology, we have yet to find the ideal dressing that can support the healing of cutaneous wounds effectively, particularly for difficult-to-heal chronic wounds such as diabetic foot ulcers, bed sores, and venous ulcers. Hence, there is a need to identify and incorporate new ideas and methods to design a more effective dressing that not only can expedite wound healing but also can reduce scarring. Calcium has been identified to influence the wound healing process. This review explores the functions and roles of calcium in skin regeneration and reconstruction during would healing. Furthermore, this review also investigates the possibility of incorporating calcium into scaffolds and examines how it modulates cutaneous wound healing. In summary, the preliminary findings are promising. However, some challenges remain to be addressed before calcium can be used for cutaneous wound healing in clinical settings.

Matched MeSH terms: Wound Healing/physiology*
Benefits of sucrose octasulfate (TLC-NOSF) dressings in the treatment of chronic wounds: a systematic review

Nair H, Venkateshwaran N, Seetharaman S S, Deng W, Uthaipaisanwong A, Galea E

J Wound Care, 2021 Apr 01;30(Sup4):S42-S52.
PMID: 33856929 DOI: 10.12968/jowc.2021.30.Sup4.S42

OBJECTIVE: Management of chronic wounds remains one of the major challenges for health professionals and patients. An evidence-based decision is important to ensure that patients are receiving the best treatment proven to reduce healing time and improve outcomes, including economic benefits and patients' health-related quality of life (HRQoL). Due to recent restrictions because of the COVID-19 pandemic, including closure of wound care centres within hospitals and a drop in patient volume, chronic wound management needs simple-to-use dressings which are still effective and evidence-based solutions. This systematic review was conducted to identify the clinical evidence available on a sucrose octasulfate dressing (TLC-NOSF, UrgoStart dressing range, Laboratoires Urgo, France) to explore its efficacy in the management of chronic wounds, particularly lower limb ulcers, diabetic foot ulcers and pressure ulcers.
METHOD: A literature search of PubMed, Cochrane Library and Google Scholar was conducted based on the PICO model (patient/population, intervention, comparison and outcomes) to retrieve publications of different levels of evidence in order to evaluate outcomes of the use of TLC-NOSF dressings.
RESULTS: A total of 21 publications of different levels, ranging from double-blind randomised control trials to case reports, involving over 12,000 patients, were identified through PubMed, with a further eight publications through Google Scholar and two publications through Cochrane Library. A total of seven results were omitted due to the lack of relevance or repetition.
CONCLUSION: All the evidence provided suggest that these dressings provide clinicians with an evidence-based option for the management of chronic wounds; that the TLC-NOSF dressings are beneficial in promoting the healing process, reducing healing times, enhancing patients' HRQoL, and in allowing a more cost-effective procedure.

Matched MeSH terms: Wound Healing/physiology*
Usage of allogeneic single layered tissue engineered skin enhance wound treatment in sheep

Adha PR, Chua KH, Mazlyzam AL, Low KC, Aminuddin BS, Ruszymah BH

Med J Malaysia, 2008 Jul;63 Suppl A:30-1.
PMID: 19024968

A major factor limiting survival following extensive thermal injury is insufficient availability of donor sites to provide enough skin for the required grafting procedures. Limitation of autologous grafting promotes the usage of allograft skin substitutes to promote wound healing. Here, we investigated the wound healing potential of allograft single layered tissue engineered skin which comprises of either keratinocytes (SLTES-K) or fibroblast (SLTES-F) with fibrin as the delivery system. Results from gross and microscopic evaluation showed our single layered tissue engineered skin constructed with keratinocytes or fibroblast after gamma radiation with the dosage of 2Gy could serve as allograft for the treatment of skin loss.

Matched MeSH terms: Wound Healing/physiology*
Dried irradiated human amniotic membrane as a biological dressing for facial burns--a 7-year case series

Bujang-Safawi E, Halim AS, Khoo TL, Dorai AA

Burns, 2010 Sep;36(6):876-82.
PMID: 20236771 DOI: 10.1016/j.burns.2009.07.001

Facial burns are common and have a significant impact on patient function and psychosocial well being. Human amnion has been used for many years as a temporary biological wound dressing in the management of partial thickness burns. The observed advantages of human amnion treatment include pain relief, ease of use, prevention of infection and acceleration of wound healing.

Matched MeSH terms: Wound Healing/physiology
Fulltext Early results of a rotation flap to treat chronic anal fissures

Singh M, Sharma A, Duthie G, Balasingh D, Kandasamy P

Asian J Surg, 2005 Jul;28(3):189-91.
PMID: 16024313

Treatment of anal fissures has changed dramatically in the past decade. This is primarily due to a better understanding of its pathophysiology and the implications of the various available options. Only a few anal fissures fail to respond to medical therapy. Sphincterotomy and anal dilatation have fallen out of favour due to the risk of incontinence. Island flaps have been proposed to address this, but 60-70% of the flap donor sites break down with complications. We propose using a rotation flap to overcome this problem.

Matched MeSH terms: Wound Healing/physiology
Poly (3-hydroxyalkanoates)-co-(6-hydroxyhexanoate) hydrogel promotes angiogenesis and collagen deposition during cutaneous wound healing in rats

Gumel AM, Razaif-Mazinah MR, Anis SN, Annuar MS

Biomed Mater, 2015 Aug;10(4):045001.
PMID: 26154416 DOI: 10.1088/1748-6041/10/4/045001

Wound management and healing in several physiological or pathological conditions, particularly when comorbidities are involved, usually proves to be difficult. This presents complications leading to socio-economic and public health burdens. The accelerative wound healing potential of biocompatible poly(3-hydroxyalkanoates)-co-(6-hydroxyhexanoate) (PHA-PCL) composite hydrogel is reported herein. The biosynthesized PHA-PCL macromer was cross-linked with PEGMA to give a hydrogel. Twenty-four rats weighing 200-250 g each were randomly assigned to four groups of six rats. Rats in group I (negative control) were dressed with sterilized gum acacia paste in 10% normal saline while PEGMA-alone hydrogel (PH) was used to dress group II (secondary control) rats. Group III rats were dressed with PHAs-PCL cross-linked PEGMA hydrogel (PPH). For the positive control (group IV), the rats were dressed with Intrasite(®) gel. Biochemical, histomorphometric and immunohistomorphometric analyses revealed a significant difference in area closure and re-epithelialization on days 7 and 14 in PPH or Intrasite(®) gel groups compared to gum acacia or PEGMA-alone groups. Furthermore, wounds dressed with PPH or Intrasite(®) gel showed evident collagen deposition, enhanced fibrosis and extensively organized angiogenesis on day 14 compared to the negative control group. While improvement in wound healing of the PH dressed group could be observed, there was no significant difference between the negative control group and the PH dressed group in any of the tests. The findings suggested that topical application of PPH accelerated the rats' wound healing process by improving angiogenesis attributed to the increased microvessel density (MVD) and expressions of VEGF-A in tissue samples. Thus, PPH has been demonstrated to be effective in the treatment of cutaneous wounds in rats, and could be a potential novel agent in the management and acceleration of wound healing in humans and animals.

Matched MeSH terms: Wound Healing/physiology
Functional Outcomes After Heel Pad Reconstruction: A Review of 7 Cases

Khai Luen K, Wan Sulaiman WA

J Foot Ankle Surg, 2017 8 27;56(5):1114-1120.
PMID: 28842095 DOI: 10.1053/j.jfas.2017.04.024

Sensate, durable heel pad reconstruction is challenging. The present study assessed the functional outcomes after heel pad reconstruction using various flap techniques at our institution. From June 2011 to June 2016 (5-year period), 7 consecutive patients underwent heel pad reconstruction for various etiologies, with 3 microvascular free flaps (42.9%; 2 musculocutaneous flaps [66.7%] and 1 contralateral medial plantar flap [33.3%]) and 4 local pedicle flaps (57.1%; 3 instep medial plantar artery flaps [75.0%] and 1 distally based reverse sural flap [25.0%]). The patient records and demographic data were reviewed, and surgically related information was obtained and analyzed. The subjective components of the American Orthopaedic Foot and Ankle Society hindfoot clinical ratings scale were used to evaluate the pain and functional outcomes. Sensation was assessed using Semmes-Weinstein monofilaments, and ulcer recurrence was recorded. The mean age of the patients was 41.7 (range 11 to 70) years, the mean defect size was 59 (range 12 to 270) cm2, and the mean follow-up duration was 22 (range 15 to 43) months. Complete flap survival was achieved without significant complications in all 7 patients. Patients treated with the sensate medial plantar artery flap recorded the highest mean American Orthopaedic Foot and Ankle Society score of 57.3 (maximum score of 60) and experienced a return of deep sensation at 6 (range 6 to 24) months and protective sensation at 1 year. This was followed by the reverse sural flap and the musculocutaneous flap. No recurrent heel ulceration was observed in our series of patients. In conclusion, the sensate medial plantar flap is a satisfactory method for coverage of small- to moderate-size heel defects.

Matched MeSH terms: Wound Healing/physiology
The Use of Engineered Bilayered Skin (MyDermTM) in the Management of Massive Skin Defect in Grade III Gustilo-Anderson Open Fracture

Mohamed Haflah NH, Ng MH, Mohd Yunus MH, Naicker AS, Htwe O, Fahmi M, et al.

Int J Low Extrem Wounds, 2017 Sep;16(3):212-216.
PMID: 28862056 DOI: 10.1177/1534734617724974

Open fracture Gustilo-Anderson grade IIIC is associated with higher risk of infection and problems with soft tissue coverage. Various methods have been used for soft tissue coverage in open fractures with large skin defect. We report a case of a patient who had grade IIIC open fracture of the tibia with posterior tibial artery injury. The patient underwent external fixation and reduction. Because of potential compartment syndrome after vascular repair, fasciotomy of the posterior compartment was performed. This wound, however, became infected and because of further debridement, gave rise to a large skin defect. A tissue engineered skin construct, MyDermTM was employed to cover this large defect. Complete wound closure was achieved 35 days postimplantation. The patient then underwent plating of the tibia for nonunion with no adverse effect to the grafted site. The tibia eventually healed 5 months postplating, and the cosmetic appearance of the newly formed skin was satisfactory.

Matched MeSH terms: Wound Healing/physiology
Fulltext Effect on interleukin-1β and interleukin-8 levels following use of fibrin sealant for periodontal surgery

Pulikkotil SJ, Nath S

Aust Dent J, 2014 Jun;59(2):156-64.
PMID: 24861389 DOI: 10.1111/adj.12178

Fibrin sealant (FS) is a biologically derived tissue adhesive for securing flaps. The aim of the present randomized controlled clinical trial was to compare early wound healing by assessing interleukin-1β (IL-1β) and interleukin-8 (IL-8) levels from gingival crevicular fluid (GCF) after using FS and suture for periodontal flap closure.

Matched MeSH terms: Wound Healing/physiology
Full-thickness skin wound healing using autologous keratinocytes and dermal fibroblasts with fibrin: bilayered versus single-layered substitute

Idrus RB, Rameli MA, Low KC, Law JX, Chua KH, Latiff MB, et al.

Adv Skin Wound Care, 2014 Apr;27(4):171-80.
PMID: 24637651 DOI: 10.1097/01.ASW.0000445199.26874.9d

Split-skin grafting (SSG) is the gold standard treatment for full-thickness skin defects. For certain patients, however, an extensive skin lesion resulted in inadequacies of the donor site. Tissue engineering offers an alternative approach by using a very small portion of an individual's skin to harvest cells for propagation and biomaterials to support the cells for implantation. The objective of this study was to determine the effectiveness of autologous bilayered tissue-engineered skin (BTES) and single-layer tissue-engineered skin composed of only keratinocytes (SLTES-K) or fibroblasts (SLTES-F) as alternatives for full-thickness wound healing in a sheep model. Full-thickness skin biopsies were harvested from adult sheep. Isolated fibroblasts were cultured using medium Ham's F12: Dulbecco modified Eagle medium supplemented with 10% fetal bovine serum, whereas the keratinocytes were cultured using Define Keratinocytes Serum Free Medium. The BTES, SLTES-K, and SLTES-F were constructed using autologous fibrin as a biomaterial. Eight full-thickness wounds were created on the dorsum of the body of the sheep. On 4 wounds, polyvinyl chloride rings were used as chambers to prevent cell migration at the edge. The wounds were observed at days 7, 14, and 21. After 3 weeks of implantation, the sheep were euthanized and the skins were harvested. The excised tissues were fixed in formalin for histological examination via hematoxylin-eosin, Masson trichrome, and elastin van Gieson staining. The results showed that BTES, SLTES-K, and SLTES-F promote wound healing in nonchambered and chambered wounds, and BTES demonstrated the best healing potential. In conclusion, BTES proved to be an effective tissue-engineered construct that can promote the healing of full-thickness skin lesions. With the support of further clinical trials, this procedure could be an alternative to SSG for patients with partial- and full-thickness burns.

Matched MeSH terms: Wound Healing/physiology*
Living bilayered human skin equivalent: promising potentials for wound healing

Mazlyzam AL, Aminuddin BS, Saim L, Ruszymah BH

Med J Malaysia, 2008 Jul;63 Suppl A:32-3.
PMID: 19024969

The angiogenic potential of native skin (NS), keratinocytes single skin equivalent (SSE-K), fibroblasts single skin equivalent (SSE-F) and bilayered skin equivalent secreting angiogenic growth factors such as transforming growth factor beta1 (TGF-beta1), vascular endothelial growth factor (VEGF), keratinocyte growth factor (KGF) and basic fibroblast growth factor (bFGF) in the in vitro systems at 24, 48, 72 hours and 7 days was compared using Enzyme-Linked Immunosorbent Assay (ELISA). Bilayered skin equivalent exhibit highest release of growth factors within 24 hours to 7 days of culture compared to NS, SSE-K and SSE-F. This proved the potential of bilayered skin equivalent in producing and sustaining growth factors release to enhance angiogenesis, fibroblasts proliferation, matrix deposition, migration and growth of keratinocytes.

Matched MeSH terms: Wound Healing/physiology*
Effect of green and ripe Carica papaya epicarp extracts on wound healing and during pregnancy

Anuar NS, Zahari SS, Taib IA, Rahman MT

Food Chem Toxicol, 2008 Jul;46(7):2384-9.
PMID: 18468758 DOI: 10.1016/j.fct.2008.03.025

The traditional use of papaya to treat many diseases, especially skin conditions and its prohibition for consumption during pregnancy has prompted us to determine whether papaya extracts both from green and ripe fruits improve wound healing and also produce foetal toxicity. Aqueous extracts of green papaya epicarp (GPE) and ripe papaya epicarp (RPE) were applied on induced wounds on mice. GPE treatment induced complete healing in shorter periods (13 days) than that required while using RPE (17 days), sterile water (18 days) and Solcoseryl ointment (21 days). Extracts were administered orally (1 mg/g body weight/day) to pregnant mice from day 10 and onwards after conception. 3 (n=7) mice and 1 (n=6) mice given RPE and misoprostol, an abortive drug, respectively experienced embryonic resorption while this effect was observed in none of the mice given GPE (n=5) and water (n=5). The average body weight of live pups delivered by mice given GPE (1.12+/-0.04 g) was significantly lower than those delivered by mice given water (1.38+/-0.02 g). In SDS-PAGE, proteins were distributed in three bands (Mr range approximately 8-29 kDa). Band intensity at Mr approximately 28-29 kDa was higher in GPE than in RPE. In contrast, band intensity at low Mr (approximately 8 kDa) was found to be higher in RPE than in GPE. Notably, the band corresponding to Mr approximately 23-25 kDa was absent in RPE. These differences in composition may have contributed to the different wound healing and abortive effects of green and ripe papaya.

Matched MeSH terms: Wound Healing/physiology
The effect of topical extract of Momordica charantia (bitter gourd) on wound healing in nondiabetic rats and in rats with diabetes induced by streptozotocin

Teoh SL, Latiff AA, Das S

Clin Exp Dermatol, 2009 Oct;34(7):815-22.
PMID: 19508570 DOI: 10.1111/j.1365-2230.2008.03117.x

Momordica charantia (MC; bitter gourd) is a traditional herb commonly used for its antidiabetic, antioxidant, contraceptive and antibacterial properties. It is also used for the rapid healing of wounds.

Matched MeSH terms: Wound Healing/physiology
Fulltext eComment: Negative pressure vacuum assisted closure therapy following cardiac surgery: safe and effective

Sachithanandan A

Interact Cardiovasc Thorac Surg, 2011 Feb;12(2):120.
PMID: 21257947 DOI: 10.1510/icvts.2010.252668A
Matched MeSH terms: Wound Healing/physiology
Fulltext A preliminary study comparing the use of allogenic chondrogenic pre-differentiated and undifferentiated mesenchymal stem cells for the repair of full thickness articular cartilage defects in rabbits

Dashtdar H, Rothan HA, Tay T, Ahmad RE, Ali R, Tay LX, et al.

J Orthop Res, 2011 Sep;29(9):1336-42.
PMID: 21445989 DOI: 10.1002/jor.21413

Chondrogenic differentiated mesenchymal stem cells (CMSCs) have been shown to produce superior chondrogenic expression markers in vitro. However, the use of these cells in vivo has not been fully explored. In this study, in vivo assessment of cartilage repair potential between allogenic-derived chondrogenic pre-differentiated mesenchymal stem cells and undifferentiated MSCs (MSCs) were compared. Bilateral full thickness cartilage defects were created on the medial femoral condyles of 12 rabbits (n = 12). Rabbits were divided into two groups. In one group, the defects in the right knees were repaired using alginate encapsulated MSCs while in the second group, CMSCs were used. The animals were sacrificed and the repaired and control knees were assessed at 3 and 6 months after implantation. Quantitative analysis was performed by measuring the Glycosaminoglycans (GAGs)/total protein content. The mean Brittberg score was higher in the transplanted knees as compared to the untreated knee at 6 months (p 0.05). This study demonstrates that the use of either MSC or CMSC produced superior healing when compared to cartilage defects that were untreated. However, both cells produced comparable treatment outcomes.

Matched MeSH terms: Wound Healing/physiology*
Comparative effects of palm vitamin E and alpha-tocopherol on healing and wound tissue antioxidant enzyme levels in diabetic rats

Musalmah M, Nizrana MY, Fairuz AH, NoorAini AH, Azian AL, Gapor MT, et al.

Lipids, 2005 Jun;40(6):575-80.
PMID: 16149736

The effect of supplementing 200 mg/kg body weight palm vitamin E (PVE) and 200 mg/kg body weight alpha-tocopherol (alpha-Toc) on the healing of wounds in streptozotocin-induced diabetic rats was evaluated. The antioxidant potencies of these two preparations of vitamin E were also evaluated by determining the antioxidant enzyme activities, namely, glutathione peroxidase (GPx) and superoxide dismutase (SOD), and malondialdehyde (MDA) levels in the healing of dermal wounds. Healing was evaluated by measuring wound contractions and protein contents in the healing wounds. Cellular redistribution and collagen deposition were assessed morphologically using cross-sections of paraffin-embedded day-10 wounds stained according to the Van Gieson method. GPx and SOD activities as well as MDA levels were determined in homogenates of day-10 dermal wounds. Results showed that PVE had a greater potency to enhance wound repair and induce the increase in free radical-scavenging enzyme activities than alpha-Toc. Both PVE and alpha-Toc, however, were potent antioxidants and significantly reduced the lipid peroxidation levels in the wounds as measured by the reduction in MDA levels.

Matched MeSH terms: Wound Healing/physiology
The effects of age on monolayer culture of human keratinocytes for future use in skin engineering

Muhd Fakhruddin BH, Aminuddin BS, Mazlyzam AL, Ruszymah BH

Med J Malaysia, 2004 May;59 Suppl B:182-3.
PMID: 15468878

Skin is the largest organ in human system and plays a vital role as a barrier against environment and pathogens. Skin regeneration is important in tissue engineering especially in cases of chronic wounds. With the tissue engineering technology, these skins equivalent have been use clinically to repair burns and wounds. Consented redundant skin samples were obtained from patients aged 9 to 65 years old. Skin samples were digested with dispase, thus separating the epidermis and the dermis layer. The epidermis layer was trypsinized and cultured in DKSFM in 6-well plate at 37 degrees C and 5% CO2. Once confluent, the culture were trypsinized and the cells were pooled. Cells were counted using haemacytometer. Doubling time and viability were calculated and analysed. From the result, we conclude that doubling time and viability of in vitro keratinocytes cultured in DKSFM media is not age dependant.

Matched MeSH terms: Wound Healing/physiology
The use of glycerol-preserved skin allograft in conjunction with reconstructive and flap surgery: seven years of experience

Saad AZ, Halim AS, Khoo TL

J Reconstr Microsurg, 2011 Feb;27(2):103-8.
PMID: 20976667 DOI: 10.1055/s-0030-1268208

Major reconstructive surgery may be extensive and prolonged, and it may cause edema and compromise the flap pedicle if closed under tension. Glycerol-preserved skin allograft (GPA) can provide a means for tension-free closure and temporary cover of the wound. Seven years of analysis on GPA used in conjunction with major reconstruction was undertaken to highlight its indications, results, and outcomes. Forty-seven patients were included, aged between 9 and 73 years. Majority of patients had reconstruction following tumor resection and trauma. The main indication for use of GPA was temporary, loose cover of the wound in 44% of cases; flap pedicle protection in 31% of cases; donor site wound cover in 10%; flap monitoring in one case; and management of flap-related complications in 6% of cases. Free flap reconstruction was performed in 72% of cases. In conclusion, GPA is a useful adjunct in reconstructive surgery. It can be used temporarily to allow tension-free wound closure, as well as to protect the flap pedicle until edema subsides and the pedicle becomes stable. This latter approach allows secondary wound closure and good esthetic outcome.

Matched MeSH terms: Wound Healing/physiology
Fulltext Wound-healing potential of the fruit extract of Phaleria macrocarpa

Abood WN, Al-Henhena NA, Najim Abood A, Al-Obaidi MM, Ismail S, Abdulla MA, et al.

Bosn J Basic Med Sci, 2015 05 12;15(2):25-30.
PMID: 26042509 DOI: 10.17305/bjbms.2015.39

The wound-healing potential of Phaleria macrocarpa was evaluated by monitoring the levels of inflammatory mediators, collagen, and antioxidant enzymes. Experimentally, two-centimeter-wide full-thickness-deep skin excision wounds were created on the posterior neck area of the rats. The wounds were topically treated with gum acacia as a vehicle in the control group, intrasite gel in the reference group, and 100 and 200 mg/mL P. macrocarpa ‎fruit extract in the treatment group. Granulation tissues were excised on the 15th day and were further processed for histological and biochemical analyzes. Wound healing was evaluated by measuring the contractions and protein contents of the wounds. Cellular redistribution and collagen deposition were assessed morphologically using Masson's trichrome stain. Superoxide dismutase (SOD) and catalase (CAT) activities, along with malondialdehyde (MDA) level were determined in skin tissue homogenates of the dermal wounds. Serum levels of transforming growth factor beta 1 (TGF-β1) and tumor necrosis factor alpha (TNF-α) were evaluated in all the animals. A significant decrease in wound area was caused by a significant increase in TGF-β1 level in the treated groups. Decrease in TNF-α level and increase in the collagen formation were also observed in the treated groups. Topical treatment with P. macrocarpa fruit extract increased the SOD and CAT activities in the healing wounds, thereby significantly increasing MDA level. The topical treatment with P. macrocarpa fruit extract showed significant healing effect on excision wounds and demonstrated an important role in the inflammation process by increasing antioxidant enzyme activities, thereby accelerating the wound healing process and reducing tissue injury.

Matched MeSH terms: Wound Healing/physiology
Annona muricata leaves accelerate wound healing in rats via involvement of Hsp70 and antioxidant defence

Moghadamtousi SZ, Rouhollahi E, Hajrezaie M, Karimian H, Abdulla MA, Kadir HA

Int J Surg, 2015 Jun;18:110-7.
PMID: 25899210 DOI: 10.1016/j.ijsu.2015.03.026

Annona muricata, a member of the Annonaceae family, is commonly known as soursop and graviola. The leaves of this tropical fruit tree are widely used in folk medicine against skin diseases and abscesses, however there is no scientific evidence justifying the use of A. muricata leaves. The aim of the present study is to evaluate the wound healing potential of ethyl acetate extract of A. muricata leaves (EEAM) towards excisional wound models in rats.

Matched MeSH terms: Wound Healing/physiology

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